Fluvastatin Sodium salt of formula I (relative stereochemistry) is marketed by Novartis under the trade name of Lescol and belongs to a class of anti-hyperlipidemic agents called statins. Such compounds are HMG-COA reductase inhibitors, i.e. inhibit the enzyme that reduces 3-hydroxy-3-methylglutaric acid to mevalonic acid, thus blocking the biosynthesis of cholesterol and lowering its level in the bloodstream. Most statins resemble mevalonic acid in the sense that they contain the 3,5-dihydroxy carboxylate function, fooling the enzyme to binding to the drug and therefore inhibiting it.

The product patent for Fluvastatin is EP 114027, in which several synthetic routes are described. The last 2 steps (reduction followed by saponification) of the preferred process are better described in the process patent EP 363934, in which the synthesis set forth in Scheme 1 (relative stereochemistry) is described; the drug substance is then obtained by lyophilization of its aqueous solution.

This patent claims a specific order of addition of the reactants in the stereoselective reduction from III to II, in order to achieve a high level of syn stereoselectivity and minimize the unwanted diastereomer, the so called anti isomer IV (relative stereochemistry).

This is well explained in the paper written by Novartis' process research and development group “The Story of Lescol: From Research to Production”, Org. Process Res. Dev. 2001, 5, 519-527: in the introduction they report that the most difficult challenge was “to form the 3,5-diol exclusively in the syn configuration”. This unwanted anti diastereomer is actually the main impurity of Fluvastatin Sodium salt and its ester precursors, as confirmed by the United States Pharmacopoeia monograph of Fluvastatin (Official Monographs, USP 28, First Supplement, USP-NF, 3234), which sets a limit of 0.8% (HPLC) for this impurity and a much lower limit of 0.1% for any other impurity. This high limit set by the USP, which is unusual for impurities in active pharmaceutical ingredients, must be due to the limited stability of Fluvastatin in stressed degradation studies; such limited stability is reported on page 9 of EP 907639, which uses the same HPLC method later adopted by the USP; clearly the anti isomer must be one of the main degradation products and this fact has been actually confirmed by our independent investigations. In conclusion, the content of anti isomer in the active pharmaceutical ingredient must be far below the above set limit to allow for the unavoidable degradation that takes place during storage (showed by the stability studies), i.e. the content of anti isomer must reasonably be below 0.4% and preferably below 0.2%.
Novartis apparently solved the problem of the purification of Fluvastatin Sodium from its anti isomer improving the stereoselectivity of the reduction of the carbonyl to the hydroxyl group, as claimed in EP 363934, affording an ester precursor of better quality. In “The Story of Lescol” is stated on page 526 that starting from the t-butyl ester (which is preferred over the methyl ester, since avoids a lactonization side process that causes isomerization to the anti isomer) such reduction affords a 99:1 selectivity, i.e. we must understand that the ester precursor contains about 1% of the unwanted anti isomer; this means that the ester precursor has to be recrystallized at least twice in order to achieve a reasonable degree of purity, with considerable yield loss. As a matter of fact, the authors of the paper carry on stating that: “only minimal purification occurs in the last step. The saponification leaves Fluvastatin Sodium salt in the aqueous layer, which is freeze-dried, to obtain the drug substance as a white powder”.
As shown above, there is still need of an improved process for the preparation of Fluvastatin Sodium salt that allows minimizing the content of anti isomer, without resorting to several crystallizations of its t-butyl ester precursor, which cause considerable yield loss.